The HSP90 inhibitor Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy: an in vitro and in vivo approach
The HSP90 inhibitor Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy: an in vitro and in vivo approach
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DOI：
10.1038/s41598-020-62293-4
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发表时间：
2020-04-03
影响因子：
4.6
通讯作者：
Stenerlow, Bo
中科院分区：
文献类型：
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作者：
Spiegelberg, Diana;Abramenkovs, Andris;Stenerlow, Bo
伴侣蛋白热休克蛋白90（HSP 90）的致癌客户蛋白确保无限的肿瘤生长，并参与抵抗化疗和放疗。HSP 90抑制剂Onalb启动癌蛋白的降解，也可能作为放射增敏剂。因此，本研究的目的是在体外和体内方法中评价Onalb联合外照射放疗的疗效。Onalb下调客户蛋白，导致细胞凋亡增加并引起DNA双链。在放射敏感性HCT 116和放射抗性A431细胞中，单药治疗和联合放疗可降低集落形成、增殖和迁移。在体内，连续3天Onalbib（3 x 10 mg/kg）的最小治疗方案使存活率加倍，而Onalbib与放疗（3 x 2戈伊）导致肿瘤生长显著延迟，并且与HCT 116异种移植对照组相比，存活率延长3倍。我们的研究结果表明，Onalbib与放射治疗结合时发挥协同抗癌作用，在放射敏感细胞模型中最为突出。我们推测，参与信号传导、迁移和DNA修复机制的客户蛋白的耗尽和下调是原因。因此，单独使用或与放疗联合使用Onalb可抑制肿瘤生长，并有可能改善放疗结果，延长癌症患者的总生存期。
Oncogenic client-proteins of the chaperone Heat shock protein 90 (HSP90) insure unlimited tumor growth and are involved in resistance to chemo- and radiotherapy. The HSP90 inhibitor Onalespib initiates the degradation of oncoproteins, and might also act as a radiosensitizer. The aim of this study was therefore to evaluate the efficacy of Onalespib in combination with external beam radiotherapy in an in vitro and in vivo approach. Onalespib downregulated client proteins, lead to increased apoptosis and caused DNA-double-strands. Monotherapy and combination with radiotherapy reduced colony formation, proliferation and migration assessed in radiosensitive HCT116 and radioresistant A431 cells. In vivo, a minimal treatment regimen for 3 consecutive days of Onalespib (3 x 10 mg/kg) doubled survival, whereas Onalespib with radiotherapy (3 x 2 Gy) caused a substantial delay in tumor growth and prolonged the survival by a factor of 3 compared to the HCT116 xenografted control group. Our results demonstrate that Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy, most prominent in the radiosensitive cell models. We speculate that the depletion and downregulation of client proteins involved in signalling, migration and DNA repair mechanisms is the cause. Thus, individually, or in combination with radiotherapy Onalespib inhibits tumor growth and has the potential to improve radiotherapy outcomes, prolonging the overall survival of cancer patients.